Amine salts of nopinic acid



United States Patent 3,520,920 AMINE SALTS OF N OPINIC ACID Leon Gillo, Brussels, Belgium, assiguor to Pharmatic, Inc., New York, 'N.Y., a corporation of Delaware No Drawing. Filed June 28, 1965, Ser. No. 467,712 Claims priority, application Great Britain, July 6, 1964, 27,788/64 Int. Cl. C07c 91/06 U.S. Cl. 260501.17 8 Claims ABSTRACT OF THE DISCLOSURE Hydroxy alkyl amino salts of nopinic acid as new compounds useful in pharmaceutical compositions for alleviating ulcer conditions.

This invention relates to new pharmaceutical compositions and particularly to compositions suitable for the prevention and control of ulcers and/or of the pain due to ulcers, particularly ulcers of the digestive tract, such as the ulcers of the gastro-duodenal tract, as well as the skin ulcers.

It has now been found that ,B-pinene and derivatives thereof have surprisingly very interesting pharmacological properties in the field of the prevention and control of ulcers and/ or of the pain due to ulcers.

The pharmaceutical compositions according to this invention contain, as active ingredient, at least one compound of the following general formula:

in which Z represents a C=CH group a group of the formula (|JC 0 OX in which X represents hydrogen, a cation of an alkaline metal or ammonium, a lower alkyl radical or a group of the formula /R (CH2),.N

in which 11:1 to 3 inclusive, whereas R and R', which may be similar or different, represent a lower alkyl radical, or a group of the formula in which n, R and R have the above indicated meaning. Among the compounds of the general Formula I, some compounds are known and others are now.

Thus, p-pinene or nopinene is a known compound of the formula:

mmofl I (II) which can be easily isolated from turpentine oil. B.P.:

161-163 C; [aJ =2122.

3,520,920 Patented July 21, 1970 Moreover, the nopinic acid and the alkaline metal salts thereof of the formula C O OH I OH \I/ are also known.

However, the pharmaceutical compositions may also contain, as active ingredient, compounds of the general formula I which are new compounds. These new compounds may be represented by the following general formulae:

(III) COOX / IECOH3 I/ (IV) in which X represents a lower alkyl radical or a group of the formula:

(CH2)n N in which n=1 to 3 inclusive, whereas R and R, which may be similar or different, represent hydrogen or a lower alkyl radical; and III COOH-N (CH-z)OH OH R Rio-42m in which n =1 to 3 inclusive, wheras R and R, which may be similar or diiferent, represent hydrogen or a lower alkyl radical.

Among the new compounds of Formula IV, the following may be cited as examples:

ammonium nopinate methyl nopinate (X' -CHa) ethyl nopinate (XZ-CaHs) n-propyI-nopinate (X'=nCaH1) isopropyl nopinate (X'=iS0C3H7) aminoethyl nopinate (X=-(CH2)2NH2 3 Among the new compounds of Formula (V), the following may be cited:

aminoethanol salt of nopinic acid (R=R'=H; n=2) dirnethylaminoethanol salt of nopinic acid (R R=CH diethylaminoethanol salt of nopinic acid (R:R':C H

monomethylaminoethanol salt of nopinic acid (R=H; 'R'=CH n=2) diisopropylaminoethanol salt of nopinic acid di-n-butylaminoethanol salt of nopinic acid (R=R' =11C H dimethylaminopropanol salt of nopinic acid (R=R'=CH 11:3).

This invention includes as new compounds the esters and salts of nopinic acid of the Formula IV and V, as well as the acid addition salts, such as the hydrochlorides of the compounds of the Formula IV.

The pharmaceutical compositions according to the present invention are generally intended for peroral, topical or parenteral administration. Therapeutical compositions to be administered perorally may, for example, be in the form of tablets, dragees, capsules, in which at least one compound selected among the compounds of the general Formula I is mixed with a solid pharmaceutically acceptable vehicle or excipient.

The therapeutical compositions may also be used in the form of ointments or creams for the treatment of skin ulcers, said ointments or creams containing at least one compound selected among the compounds of the Formula I mixed to an usual pharmaceutical cream or ointment base.

The therapeutical compositions can also be used in the form of liquid preparations for oral administration, especially syrups, elixirs, aqueous dispersions or solutions.

The therapeutic compositions according to the present invention can also be used in the form of solution to be administered parenterally. Solutions or suspensions for injection purpose can be prepared by using, for example, distilled water of sterile a pyrogenic water, in which at least one compound of the aforementioned Formula I is dissolved or suspended, if desired in the presence of a dissolving or stabilizing agent, such as propylene glycol.

Finally, it is possible for a compound selected among the compounds of general Formula I to be administered rectally, by incorporating it in a composition for suppositories, for example in cocoa butter.

B-pinene and the compounds of the general Formulae III, IV and II can be administered in varying doses, depending on the particular compound being used, the condition of the patient and the method of administration.

Thus, the compounds in question can be administered in doses from 50 to 600 mg. per day, in the form of several doses taken throughout the day.

The invention relates also to processes for the preparation of the new compounds represented by the Formulae 1V and V.

The alkyl esters as well as the aminoalkyl esters of nopinic acid of the Formula IV may be prepared by the usual esterification methods, such as:

1) Heating of nopinic acid in the suitable esterification alcohol, possibly in the presence of a catalyst such as hydrochloric acid or p-toluene sulphonic acid, with or without azeotropic removal of the formed water;

(2) Transesterification (3) Reaction of alkaline salt of nopinic acid with an appropriate alkyl halide or aminoalkyl halide.

The aminoalkanol salts of nopinic acid of the Formula V may be prepared by dissolving nopinic acid in an anhydrous organic solvent, by neutralizing the solution with a stoichiometric quantity of the suitable aminoalcohol dissolved in the same solvent and by concentratin to dryness.

Examples of methods for the preparation of the compounds used in the pharmaceutical compositions according to this invention, as well as several examples of pharmaceutical compositions are given below for illustrative purposes.

EXAMPLE 1 Preparation of nopinic acid This acid may be prepared by oxidation of fi-pinene by means of potassium permanganate or another oxidizing agent, the reaction being carried out in an aqueous alkaline medium, by the following procedure:

392 grams of caustic potash and 2.212 grams of potassium permanganate are dissolved in 31 liters of deionized water. While stirring vigorously, 952 grams (7 moles) of fl-pinene are added. The reaction mixture is maintained during 3 to 5 hours at a temperature of 25-30 C., by adding ice to said reaction mixture. The reaction is complete when all the potassium permanganate has reacted. The obtained suspension containing Mn0 is filtered and the precipitate is washed with deionized Water. The filtrate is concentrated under vacuum to a volume of 10 liters. 420 grams of dry sodium sulphate are then added. After standing during one night in a refrigerator, the obtained sodium nopinate is filtered and washed with ice water.

The crude sodium nopinate is dissolved in 5-6 times its weight of boiling water. The obtained solution is filtered and cooled during one night in a refrigerator. The purified sodium nopinate is then filtered, washed with ice water and dried at low temperature.

The purified sonium nopinate is suspended into 5 times its weight of water and 7 times its weight of methylene chloride. Hydrochloric acid is added to the mixture until it is strongly acid and the sodium nopinate disappears. The organic phase contains the nopinic acid. The aqueous solution is extracted three times with small fractions of methylene chloride and these fractions are combined with the organic phase. The combined organic fractions are washed with small fractions with deionized water and then dried by means of anhydrous sodium sulphate. The solution is filtered and concentrated to dryness. The residue is recrystallized from warm benzene. Yield: 25- 30%; melting point: 126127 C.; [u] =164 (methanol, 5%).

EXAMPLE 2 Preparation of alkaline metal and ammonium salts of nopinic acid These salts may be prepared by dissolving nopinic acid in methanol or another solvent. The solution is neutralized by the stoichiometric quantity of a suitable base dissolved in methanol. The methanol is removed under vacuum.

For preparing ammonium nopinate, for example, 1.8 g. of pure nopinic acid are dissolved into 20 m1. of methanol and the alcoholic solution is exactly neutralized with a titrated solution of gaseous ammonia in methanol. The methanol is removed under vacuum. The obtained ammonium nopinate is soluble in water.

EXAMPLE 3 Preparation of methylnopinate 10 g. of sodium nopinate are refluxed during 18 hours with 20 g. of methyl iodide dissolved in ml. of methanol. The mixture is then concentrated to dryness. 25 ml. of water are added to the residue and the aqueous solution is extracted several times with 20 ml. of methylene chloride. The combined extracts are dried on anhydrous sodium sulphate and the methylene chloride is evaporated. The methyl nopinate is distilled under reduced pressure. Yield: 76%. This product is a liquid which is not miscible with water, but may be dissolved in organic solvents.

EXAMPLE 4 Preparation of the dirnethylaminoethyl ester of nopinic acidand the hydrochloride thereof 7 g. of methyl nopinate prepared as described in Example 3 are heated during 12 hours at 100 C. in the presence of 50 ml. of dimethylaminoethanol and 1 g. of sodium. The excess of dimethylaminoethanol is removed by concentration to dryness. The solid residue is suspended in 100 ml. of ether. 50 ml. of water are added, whereafter methanol is added in a sufficient quantity for dissolving again the precipitate. The organic (ether) phase is collected and the aqueous phase is extracted three times with 50 ml. of ether. The ether extracts are combined and washed 5 times with 25 ml. of water. The ether solutions are dried on anhydrous magnesium sulphate. After distillation of the ether, a solid residue of dimethylaminoethyl nopinate is obtained.

For obtaining the hydrochloride of this base gaseous hydrochloric acid is bubbled into an ether solution of said base until saturation is reached. The hydrochloride precipitates: M.P. 226 C. This salt may be recrystallized from a mixture (1:3) of methanol and isopropanol. Fine white needles melting at 230-231" C. are obtained. This product is soluble in water and methanol, insoluble in ether, benzene and hexane.

EXAMPLE 5 Preparation of the aminoethyl ester of nopinic acid and the hydrochloride thereof This compound and the hydrochloride thereof is prepared as described in Example 4 from methyl nopinate, aminoethanol and sodium.

The hydrochloride melts at 146 C.

EXAMPLE 6 Preparation of the monomethylaminoethyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Example 4 from methyl nopinate, monomethylaminoethanol and sodium.

The ester melts at 144-145 C. The hydrochloride melts at 141143 C. after recrystallization from acetone.

EXAMPLE 7 Preparation of the diisopropylaminoethyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Example 4 from methyl nopinate, diisopropylaminoethanol and sodium. The hydrochloride melts at 179-180 C. after recrystallization from a mixture of benzene and acetone.

EXAMPLE 8 Preparation of the di-n-butylaminoethyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Example 4 from methyl nopinate, di-n-butylaminoethanol and sodium. The hydrochloride cannot be crystallized.

EXAMPLE 9 Preparation of the dimethylaminopropyl ester of nopinic acid and the hydrochloride thereof These compounds are prepared by the process described in Examples 4 from methyl nopinate, dimethylaminopropanol and sodium. The hydrochloride melts at 90-91 C.

EXAMPLE 10 Preparation of the dimethylaminoethanol salt of nopinic acid 18.4 g. of nopinic acid are dissolved in 100 ml. of methylene chloride and 8.9 g. of dimethylaminoethanol EXAMPLE 11 Preparation of the aminoethyl salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and aminoethanol. After recrystallization from a mixture of ethanol and benzene, the compound melts at 155 C.

EXAMPLE 12 Preparation of the monomethylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and monoethylaminoethanol. This compound melts at 99-100 C. after recrystallization from benzene.

EXAMPLE 13 Preparation of the diethylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and diethylaminoethanol. This compound melts at 6667 C. (benzene).

EXAMPLE 14 Preparation of the diisopropylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and diisopropylaminoethanol. The compound melts at 7273 C. after recrystallization from ethanol.

EXAMPLE 15 Preparation of the di-n-butylaminoethanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and di-n-butylaminoethanol. The white glasey compound cannot be recrystallized.

EXAMPLE 16 Preparation of the dimethylaminopropanol salt of nopinic acid This compound is prepared as described in Example 10 from nopinic acid and dimethylaminopropanol. The pasty white product obtained by this process cannot be recrystallized.

EXAMPLE 17 Tablets of nopinic acid derivative Mg. Nopinic acid derivative 100 Starch 100 Talc 50 Magnesium stearate 5 EXAMPLE 18 Vial for intramuscular injection Nopinic acid derivative100 mg. Buffering phosphate to pH7.5 Apyrogenic water q.s. ad.-1 m1.

EXAMPLE 19 Suppositories Nopinic acid derivative-100 mg. Cocoa butter q.s. ad.-1 suppository 7 EXAMPLE 20 Ointment G. Nopinic acid derivative 10 Ointment base (sodium lauryl sulfate, cetyl alcohol,

petrolatum) 90 In Examples 17, 18, 19 and 20, the nopinic acid derivative is preferably the dimethylaminoethanol salt of nopinic acid or the hydrochloric of dimethylaminoethyl nopinate.

Many pharmacological tests have been made with the fi-pinene, nopinic acid and derivatives thereof of Formulae I, II, II, IV and V, particularly with the dimethylaminoethanol salt of nopinic acid (S.N.D.).

Tests made on rats in order to determine the preventive anti-ulcer action of the compounds of Formulae I, H, III, IV or V, have shown that these compounds prevent the gastric ulcer caused by intermittent electrization of rats.

Extensive tests have also shown that said compounds have a cicatrizing effect on ulcers, such as hemorrhagic gastric ulcers and skin ulcers.

It has also been found that these compounds possess a strong antispasmodic and anticholinergic activity which is very useful in the therapy of the prevention and control of ulcers.

Other tests have also shown that the compounds reduce the gastric secretion and diminish the acidity of the gastric juice, said effects being favourable for the ulcer therapy.

All the esters and salts of nopinic acid of the Formulae IV and V are especially active, the compounds wherein R and R represent identical methyl, ethyl, or propyl groups being the most active compounds, The best compound seems to be the dimethyl-aminoethanol salt of nopinic acid (called S.N.D.).

Clinical tests have also been made and have shown that SND has a very strong and consistent antalgic activity on the gastro-duodenal ulcer, when the patients receive 300 to 400 mg. of SND per day (6X or 8X 50 mg.). In several cases, a curative effect on the ulcer itself has been found.

What I claim is: 1. Compound corresponding to the general formula:

I ooonm wnnnon References Cited Winstein et al.: JACS 77, 3054-61 (1955). Eigenmann et al.: JACS 81, 3440-42 (1959).

LORRAINE A. WEINBERGER, Primar Examiner P. J. KILLOS, Assistant Examiner U.S. Cl. X.R. 

